EGFR inhibition reverses resistance to lenvatinib in hepatocellular carcinoma cells

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Lenvatinib is approved as a first-line treatment for unresectable HCC. The therapeutic duration of lenvatinib is limited by resistance, but the underlying mechanism is unclear. To establish lenvatinib-resistant cells, Hep3B cells were initially treated with 3 µM lenvatinib. The concentration was gradually increased by 1 µM or 0.5 µM per week and it reached to 7.5 µM 2 months after the initial exposure to lenvatinib. The biological characteristics of these cells were analyzed by ERK activation in the MAPK signaling pathway and a human phospho‐receptor tyrosine kinase (RTK) antibody array. Factors possibly related to lenvatinib resistance were analyzed using inhibitors, and cell proliferation was analyzed. We established lenvatinib-resistant HCC cells (LR cells) by long-term exposure to lenvatinib. Lenvatinib reduced ERK activation in the parent cells, but not in the LR cells. RTK array analysis showed that the activities of EGFR and insulin-like growth factor 1 receptor (IGF1R)/insulin receptor (INSR) were significantly increased in LR cells, whereas the activities of other RTKs were unchanged. Erlotinib, a widely used EGFR inhibitor, downregulated ERK activation in LR cells. The proliferation of LR cells will also be affected when lenvatinib is combined with erlotinib to treat LR cells. In contrast, inhibition of IGFR/INSR did not affect ERK activation or cell proliferation. Scavenging of reactive oxygen species (ROS) ameliorated the enhanced EGFR activation in LR cells. Lenvatinib resistance was induced by enhanced EGFR activation, possibly via ROS accumulation, in lenvatinib- resistant cells. These findings may enable the development of lenvatinib combination therapies for HCC.

Pharmaco-proteogenomic characterization of liver cancer organoids for precision oncology

“…S4, E and F), suggesting the necessity to compare the efficacy and underlying mechanisms of different drugs against the same targets. To explore whether the LICOB pharmaco-proteogenomic data are consistent with well-studied drug resistance mechanisms, we investigated lenvatinib response and the epidermal growth factor receptor (EGFR)–related pathways that confer resistance to lenvatinib treatment in HCC ( 26 , 27 ). We found that lenvatinib resistance (high AUC) was positively correlated with high abundance of proteins and negatively correlated with DNA methylation of genes associated with EGFR tyrosine kinase inhibitor resistance (fig.…”

Combination of Vitamin C and Lenvatinib potentiates antitumor effects in hepatocellular carcinoma cells in vitro

“…In specific, inhibition of fibroblast growth factor receptor (FGFR) by Lenvatinib treatment leads to feedback activation of the EGFR-PAK2-ERK5 signaling axis. The combination of the EGFR inhibitor Gefitinib or Erlotinib and Lenvatinib displays enhanced anti-proliferative effects ( He et al, 2022 ; Jin et al, 2021 ). HGF/c-MET signaling is closely associated with drug resistance in cancer.…”

The action and resistance mechanisms of Lenvatinib in liver cancer

“…To start, researchers knew that Lenvatinib works to decrease ERK phosphorylation to inactivate the MAPK pathway and prevent cell growth. However, in resistant cell lines, there was an increase in ERK phosphorylation 32 . The cause of this discrepancy was narrowed down to two genes, one of them being EGFR.…”